CN1066270A

CN1066270A - Medicinal compound

Info

Publication number: CN1066270A
Application number: CN92103160A
Authority: CN
Inventors: J·M·格林; H·M·汉金斯; G·A·史蒂文森; D·D·沃思
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1991-04-29
Filing date: 1992-04-27
Publication date: 1992-11-18
Anticipated expiration: 2007-04-27
Also published as: NO179504C; HU213613B; HU9201398D0; BR9201540A; CS127792A3; ZA922776B; TW315371B; CA2067275C; HU215917B; KR920019364A; FI101795B; CN1030611C; RU2045953C1; NO921617D0; FI921876A0; FI921877A0; JP3135672B2; NZ242505A; AU1525792A; DE69211220T2

Abstract

The invention discloses acetone, 1-ethanol, 1-propyl alcohol and the 2-propyl alcohol solvate of dirithromycin, it provides the effective means of unpack format II dirithromycin.The method of isolating form II dirithromycin from solvate or form I dirithromycin is provided.The method that makes form II dirithromycin from non-solvative dirithromycin also is provided.

Description

Medicinal compound

The present invention relates to the semisynthetic drug chemistry, and relate to the solvation form of new large ring lactone antibiotic compounds.Specifically, the invention provides large ring lactone antibiotic compounds 9-deoxidation-11-deoxidation-9, acetone, 1-propyl alcohol, 2-propyl alcohol and the 1-butanols solvate of 11-{ imino-[2-(2-methoxy ethoxy) ethylidene] oxygen base }-(9S)-erythromycin [dirithromycin (dirithromycin) hereinafter referred to as], this stable solvate provides the effective ways that separate pharmaceutically acceptable dirithromycin with extreme high purity with productive rate.

Dirithromycin is to be derived and next large ring lactone antibiotic compounds by erythromycin.This antibiotic is described in United States Patent (USP) the 4th, 048, explanation among the embodiment 9 of No. 306 (authorizing Boehringer Ingelheim).The field of activity of described antibiotic is identical with erythromycin approximately; But the advantageous characteristic of dirithromycin is when antibiotic concentration keeps low-level in the blood plasma, and it can provide the antibiotic activity of high density in tissue.Up to now, the separation of this antibiotic is very difficult always and very ineffective.

The applicant finds that there are two kinds of forms in dirithromycin, and available X-light powdery diffractometry offers an explanation out.We are designated as form I and form ii with these two kinds of forms.Form I dirithromycin mainly has following X-light powdery diffractometry spectrum, and wherein d represents spacing; I/Io represents relative intensity:

d（

） I/Io

11.28 1.00

9.81 0.35

8.53 0.76

7.67 0.23

7.12 0.02

6.94 0.02

6.66 0.10

6.39 0.09

5.97 0.21

5.65 0.69

5.42 0.67

5.18 0.23

4.98 0.08

4.83 0.31

4.64 0.07

4.43 0.40

4.26 0.17

4.14 0.05

4.06 0.15

3.86 0.15

3.76 0.17

3.62 0.10

3.50 0.08

3.43 0.03

3.35 0.07

3.04 0.07

2.95 0.02

2.88 0.02

d（

） I/Io

2.84 0.02

2.71 0.03

2.66 0.02

2.58 0.03

Contrast therewith, form ii dirithromycin have following X-light powdery diffractometry spectrum in fact, and wherein d represents spacing, and I/Io represents relative intensity:

d（

） I/Io

14.17 0.02

10.43 0.11

9.65 1.00

8.86 0.84

8.18 0.54

7.07 0.33

6.99 0.10

6.84 0.21

6.59 0.03

6.24 0.05

6.07 0.29

5.97 0.19

5.77 0.06

5.54 0.36

5.50 0.47

5.45 0.26

d（） I/Io

5.13 0.22

5.11 0.29

4.84 0.29

4.75 0.47

4.72 0.42

4.50 0.62

4.44 0.31

4.24 0.20

4.20 0.05

4.11 0.17

4.09 0.18

3.92 0.14

3.87 0.12

3.83 0.12

3.73 0.06

3.55 0.08

3.49 0.15

3.46 0.07

3.42 0.11

3.33 0.05

3.17 0.04

3.11 0.02

2.96 0.04

2.83 0.02

2.74 0.04

2.57 0.03

Form I crystal can be by dirithromycin acetonitrile solventization, then solvate is exposed to air or vacuum-drying and is separated.The preparation method of form I dirithromycin has detailed description in the United States Patent (USP) the 4th, 048,306 of Boehringer Ingelheim, this patent is incorporated this paper as a reference into.The shortcoming of form I is that it is metastable.The pure form ii crystal of preferably isolating dirithromycin is to guarantee the homogeneity of product.The inventive method by convenient, effectively, the economic and separation method isolating form ii dirithromycin that provides performance to improve greatly smoothly.

Solvate be formed on mechanism with high motherwort specificity.We know that dirithromycin crystallization from acetonitrile becomes the solvation crystal, and still, the acetonitrile solvate of dirithromycin is known to be unsettled.Referring to P.Lugar, R.Mainer, 9-deoxidation-11 deoxidations-9-11-imino-(2-(2-methoxy ethoxy) ethylidene) oxygen base)-(9S)-and the molecular structure of erythromycin, Journal of Crystal and Molecular Structure, 9,329(1979).

One aspect of the present invention provides acetone, 1-butanols, 1-propyl alcohol and the 2-propyl alcohol solvate forms of dirithromycin.The invention provides the separation method of pure form ii dirithromycin, it comprises: make slurries under one of solvate of the present invention is stirred in the solvent that contains about 40% to 100% water, obtain pharmaceutically pure dirithromycin solid.The form ii dirithromycin of purifying is substantially free of form I dirithromycin.

Another aspect of the present invention is the separation method that the form ii dirithromycin further is provided, it is included in the solvent that contains about 80% to 100% water, stir down form I dirithromycin is made slurries, wherein solvent temperature is about 40 ℃ to about 80 ℃, obtains pharmaceutically pure dirithromycin solid.The method that obtains the form ii dirithromycin that provides on the one hand more of the present invention, it is included in dissolving intermediate dirithromycin (as solvate or form I) in the ethyl acetate, makes the form ii dirithromycin.Wherein the temperature of ethyl acetate is that about room temperature is to about 80 ℃.Provided by the invention is the form ii dirithromycin of purifying on the other hand.

All above-mentioned X-ray powder diffraction spectrums all are with the Nicolet12V powder diffractometer that the graphite monochromator is housed, and the copper radiation is the 1=1.5418/ dust.Should be understood that intensity level changes because of specimen preparation is different with instrument.

The invention provides the effective ways of preparation form ii dirithromycin.The form ii dirithromycin can be by 1-butanols, 1-propyl alcohol or 2-acetone solvate or the preparation of form I of dirithromycin.New compound, promptly the solvate of dirithromycin is by removing impurity, and helps to isolate pharmaceutically acceptable dirithromycin, and this can observe by the HPLC color atlas.

Dirithromycin is dissolved in to contain in about 0% to 80% water and about 20% to 100% non-aqueous solvent can forms solvate.Non-aqueous solvent should be corresponding with the dirithromycin solvation product of wishing to get.Like this, when hope obtained acetone solvate, solvent mixture should be water and acetone.The temperature of mixture should be room temperature to 90 ℃, and mixture was answered stir about 20 minutes or the longer time.The react completely degree of required reaction times with temperature of reaction, pressure and hope changes.Reaction process can be followed the tracks of with x-ray powder diffraction technique.Preferred reaction conditions comprises that temperature of reaction is about 50 ℃ to about 90 ℃; Reaction times is about 30 minutes or longer time.The solid solvent thing form of dirithromycin can be with ordinary method by crystallization in the solution, described method comprise cooling or freezing, add crystal seed, evaporation section solution or add entry or organism (for example: hexane) to promote crystallization.Solid can separate with the centrifugal ordinary method by comprising filtering.The solid of separating can be with washing to improve purity.But the wet cake of solvate drying or conduct is used for subsequent reactions or sepn process.

Perhaps, can in the forming process of dirithromycin, form solvate.This method comprises the methoxy ethoxy with 2-(2-) Equivalent of acetaldehyde or its hydrate or hemiacetal form is dissolved in acetone, 1-propyl alcohol or the 2-propyl alcohol.Selected solvent should be based on the dirithromycin solvate forms of hope.Stir down, with 9(S)-erythromycin amine is added in the reaction mixture.The preferred dense motherwort of erythromycin amine is about 0.2 mole to about 0.7 mole.The concentration of hemiacetal and erythromycin amine can be in the change of wide range; But, when the mol ratio of aldehyde and erythromycin amine greater than 1.1 the time, reaction efficiency is the highest.To react stir about 30 minutes to about 20 hours.Reaction times should can carry out the longer time based on the degree that reacts completely of hope.Reaction can be carried out in nitrogen atmosphere.The crystallization of solvate can be by including, but is not limited to cool off, add crystal seed and evaporating solvent is finished in interior ordinary method.Make crystallization spend the night and ice bath in stir and can increase recovery percent.Solid can separate with ordinary method.Isolating solid is can be as described above dry or use with the form of wet cake.

The acetone of dirithromycin, 1-butanols, 1-propyl alcohol and 2-propyl alcohol solvate forms can be used to unpack format II dirithromycin.The slurrying in the solvent that contains about 80～100% water and about 0%～20% non-aqueous solvent of above-mentioned 4 kinds solvate will be selected from.Non-aqueous solvent should should be selected from acetone, 1-butanols, 1-propyl alcohol and 2-propyl alcohol corresponding to the solvate forms of product.Most preferred composition is about 95% to about 100% water.Slurries stirred 2.5 hours down or the longer time for extremely about 80 ℃ in about room temperature.Temperature can change according to the speed of reaction of pressure and expectation.The situation that reaction is carried out can monitor with x-ray powder diffraction technique and differential thermal analysis.Solid form II dirithromycin can be with comprising vacuum filtration, simple filtration or the separation of centrifugal ordinary method.Solution washing solid that one of water or described four kinds of solvents and water are formed and drying.

Perhaps, can make the form ii dirithromycin by form I dirithromycin.With slurrying of form I dirithromycin and heating, use the method for the solvation form of above-mentioned dirithromycin that form ii is separated.Preferred temperature range is about 45 ℃ to about 80 ℃.The solid phase prod of this method is stable form ii dirithromycin, vacuum available baking oven or other known method drying.

Perhaps, make form ii by the method that is dissolved in ethyl acetate or the toluene by dirithromycin, dirithromycin solvate or the form I dirithromycin of non-solventization.Preferred dirithromycin concentration is about 0.10 mole to about 0.28 mole.Concentration can change according to temperature, pressure, time and stirring extent.The crystallization of form ii dirithromycin can be finished by ordinary method, comprises solvent evaporation, adds crystal seed, cooling and interpolation antagonism solvent (for example normal heptane or octane).Solid can separate with ordinary method.Isolating solid is with resisting solvent wash to improve purity.

The effective dry method comprises vacuum drying oven drying, air oven or simple vacuum drier drying.Solvate at room temperature is stable and is able to take vacuum-drying.When adopting vacuum-drying, must be noted that and avoid solvate to decompose.The preferred drying conditions of acetone solvate is dry about 40 ℃ to about 50 ℃ an of vacuum drying oven, is about 30 ℃ to 40 ℃ for the vacuum drying oven drying of isopropanol solvate.The preferred drying conditions of form ii dirithromycin is the vacuum drying oven drying under about 45 ℃ to about 55 ℃.

Self-evident, in the preparation of the preparation of solvate or form ii dirithromycin, the concentration of dirithromycin is not key factor.In the formation of solvate, the preferred concentration of dirithromycin is about 0.1 to about 0.2 molconcentration, and when unpack format II dirithromycin, the preferred concentration range for of solvate is that about 0.1 molconcentration is to about 0.2 molconcentration.

Solvate of the present invention is to have the fixing real solvate of forming, and consists of about 1 solvent molecule of per molecule dirithromycin.Solvate of the present invention is particularly useful, because they at room temperature are stable.They are very useful during at the purifying of dirithromycin with as the subsequent reactions intermediate product.

The following example further specifies the present invention.Efficiency value representative in the following example is with respect to the product purity of no water quality standard.Owing to contain 5% to 10% solvent, if sample is compared with the standard substance with same solvent content, the efficiency value of report is then low than practical effect.The value of total correlation material (TRS) is analyzed with HPLC, and the UV of employing 205nm detects and determines.

Following form bus dirithromycin (form I) and four kinds of solvents ¹³C NMR measured value.The NMR spectrum of dirithromycin solvate is at 75.4MHz, with 100mg/ml concentration, measures in deuterochloroform.Chemical shift is with respect to deuterochloroform (77.00ppm).Dirithromycin NMR spectrum is at 75.4MHz, and concentration is 50mg/mol, measures in the deuterochloroform that contains 1% tetramethylsilane.Chemical shift is with reference to deuterochloroform (77.00ppm).Attention has a structural formula that bears serial numbers after NMR stave lattice.

Numbering dirithromycin propanol isopropanol propyl carbinol acetone

1 176.99 176.95 176.95 176.95 176.94

2 44.39 44.39 44.40 44.40 44.40

3 76.88 76.81 76.82 76.81 76.81

4 44.58 44.51 44.52 44.51 44.52

5 79.17 79.07 79.08 79.07 79.08

6 74.53 74.51 74.51 74.52 74.49

Numbering dirithromycin propanol isopropanol propyl carbinol acetone

7 39.28 39.19 39.20 39.19 39.21

8 29.39 29.33 29.34 29.33 29.34

9 66.03 65.95 65.96 65.96 65.96

10 27.57 27.51 27.52 27.51 27.51

11 72.75 72.74 72.74 72.76 72.71

12 74.37 74.31 74.32 74.32 74.31

13 76.44 76.37 76.37 76.37 76.37

14 21.41 21.34 21.34 21.34 21.35

15 11.23 11.17 11.18 11.17 11.18

16 82.81 82.54 82.66 82.63 82.73

17 71.99 71.90 71.91 71.90 71.93

18 72.90 72.84 72.85 72.85 72.84

19 71.07 70.95 70.96 70.94 70.99

20 49.21 49.15 49.16 49.16 49.15

21 12.91 12.85 12.86 12.85 12.86

22 9.01 8.95 8.96 8.95 8.96

23 24.75 24.67 24.68 24.67 24.69

24 20.77 20.74 20.74 20.74 20.73

25 14.15 14.09 14.10 14.10 14.10

26 14.85 14.83 14.83 14.84 14.81

1′ 101.00 100.93 100.94 100.94 100.93

2′ 71.09 71.04 71.04 71.05 71.03

3′ 65.01 64.91 64.93 64.91 64.94

4′ 28.92 28.90 28.89 28.91 28.87

5′ 69.43 69.36 69.37 69.37 69.37

6′ 21.09 21.03 21.03 21.03 21.03

N（CH ₃） ₂40.40 40.34 40.35 40.34 40.34

1″ 94.35 94.30 94.31 94.31 94.30

2″ 34.46 34.39 34.40 34.40 34.40

3″ 72.72 72.68 72.68 72.68 72.68

4″ 78.47 78.41 78.42 78.41 78.42

5″ 65.77 65.72 65.73 65.73 65.72

6″ 18.39 18.33 18.34 18.33 18.34

7″ 21.86 21.83 21.83 21.83 21.83

8″ 58.99 58.93 58.93 58.93 58.94

Solvate 1 10.8 25.27 13.78 30.78

Solvate 2 25.8 64.16 18.85 206.62

Solvate 3 64.43 34.80

Solvate 4 62.48

Embodiment 1

The acetone solvate of dirithromycin

With 4.9g 2-(2-methoxy ethoxy) half acetal is dissolved in the 60ml reagent pure acetone.Stir and add 20.0g(9S down)-erythromycin amine A.Stirred 2 hours in the nitrogen atmosphere under the room temperature.In mixture, be sprinkled into the dirithromycin crystal seed, stir under the room temperature and spend the night.

In ice bath, mixture was stirred 1 hour.The filtering separation solid is also used the washing of 20.0ml cold acetone.Solid wet cake resuspending is in 40ml acetone.The mixture of making slurry was again stirred 1 hour down at about 0 ℃～5 ℃.The filtering separation solid is with the washing of 20.0ml cold acetone.With solid dried overnight in 50 ℃ of vacuum drying ovens.Identify that with x-ray powder diffraction instrument and NMR spectrum this product is the acetone solvate of dirithromycin, the compound ultimate production is 17.68g(77.8%)

Usefulness: 91.6%

Be 12.2% before the TRS:2.9%(resuspending)

Embodiment 2

The acetone solvate of dirithromycin

10.0g dirithromycin sample is added to 30ml to be contained in the solvent mixture of 90% acetone and 10% water.The reaction mixture reflux adds the 10ml solvent again to dissolve remaining solid.68ml 58-60 ℃ water stirring is added in this limpid colourless solution down.Reaction mixture stirred 0.5 hour down in 58 ℃, and thing to be mixed is cooled to room temperature (about 2 hours).The refrigerative mixture is inserted ice bath and stirred 2 hours, the filtering separation solid, with 67% cold water of 20ml: the washing of 33% acetone mixture, isolating solid spends the night in 40 ℃ of following vacuum-dryings.Identify with X-ray powder diffraction and to know that product is an acetone solvate.

Overall yield: 87.1%

Usefulness: 87.3%

TRS:1.92%(starting point erythromycin is 4.51%)

Embodiment 3

The acetone solvate of dirithromycin

The 10.0g dirithromycin is added in the mixed solvent that 55ml is made up of 90% acetone and 10% water.The reacting by heating mixture boils off the 23ml solvent.This colourless transparent solution stirred 0.5 hour down at 58-60 ℃, and 52ml moisture is become many little five equilibriums, was added in the solution in 30 minutes of heated and stirred.Allow reaction mixture be cooled to room temperature.The refrigerative mixture places ice bath and stirred 0.75 hour.The filtering separation solid, with 67% cold water of 20ml: the washing of 33% acetone mixture, isolating solid spends the night in 40 ℃ of vacuum-dryings.Identify with X-ray powder diffraction and to know that product is an acetone solvate.

Overall yield: 92.6%

Usefulness: 89.0%

TRS:1.93%(starting point erythromycin is 4.51%)

Embodiment 4

The acetone solvate of dirithromycin

9g form I dirithromycin is added in the 27ml acetone, and reaction mixture is heated to 50 ℃, stirs 2.5 hours, allows reaction mixture be cooled to 5 ℃ and stirred 40 minutes down at 5 ℃.The filtering separation solid is with 5 ℃ of washing with acetones of 20ml.Sample is dry in 50 ℃ of vacuum drying ovens.Product is accredited as acetone solvate through X-ray powder diffraction.

Productive rate: 77%

Embodiment 5

The 1-propyl alcohol solvate of dirithromycin

The 5g dirithromycin is added in the mixed solvent of being made up of 5ml water and 23ml 1-propyl alcohol.Solution is heated to boil up to the reaction mixture volume be 10ml, stirs to add the dirithromycin crystal seed down.Allow reaction mixture be cooled to room temperature, stir adding 20ml water down.Filter to isolate solid, washing (5ml * 3).Sample is dry in vacuum drier.Product is identified through X-ray powder diffraction and NMR and is known and be 1-propyl alcohol solvate.

Productive rate: 77%

Embodiment 6

The 1-propyl alcohol solvate of dirithromycin

The 10.0g dirithromycin is dissolved in the mixed solvent of being made up of 18ml 1-propyl alcohol and 12ml water.Mixture heating up to 50 ℃ is with the dissolving residual solid.Solution stirred 0.5 hour down in about 50 ℃.In 30 fens clock times of heated and stirred, slowly add 30ml water again.Allow reaction mixture be cooled to room temperature.The refrigerative mixture places ice bath to stir 1.0 hours.The filtering separation solid, 67% water and 33% 1-acetone mixture washing, the isolating solid cold with 20ml spend the night in 35 ℃ of vacuum-dryings.Warp ¹H NMR spectrum is measured and is known that product is the 1-propyl alcohol solvate of dirithromycin.

Overall yield: 77.6%

Usefulness: 89.9%

Embodiment 7

The 2-propyl alcohol solvate of dirithromycin

The 5g dirithromycin is added in the mixed solvent of being made up of 5ml water and 23ml 2-propyl alcohol.Solution is heated to 55 ℃ makes the solid dissolving.Reaction mixture is heated to 83 ℃, and allowing it seethe with excitement until the reaction mixture volume is 10ml.Stir and add the dirithromycin crystal seed down.Allow reaction mixture be cooled to room temperature, add 3ml water under stirring.The filtering separation solid, washing (5ml * 3).The product drying also is accredited as its 2-propyl alcohol solvate through NMR spectrum and x-ray powder diffraction.

Embodiment 8

The 1-butanols solvate of dirithromycin

The 5g dirithromycin is added in the mixed solvent of being made up of 5ml water and 40ml 1-butanols.Solution is heated to boils, keeping boiling is 15ml up to the reaction mixture volume.To be cooled to room temperature under the reaction mixture stirring.In stirred mixture, add the dirithromycin crystal seed.Reaction mixture was stirred 10 minutes, add the 40ml hexane with the precipitation solvent thing.Mixture stirred under room temperature 5 minutes.Separate solid, deionization washing (50ml * 3).Sample is dry in vacuum drier.Know through X-ray powder diffraction and the evaluation of NMR spectrum: product is a 1-butanols solvate.

Embodiment 9

By acetone solvate erythromycin form ii discretely

The 20g non-solvative dirithromycin is added in the mixed solvent of being made up of 81ml acetone and 9ml water.Solution is heated to about 60 ℃.Keeping 60 ℃ is 35ml until the reaction mixture volume.With adding 100ml water in 1 hour lentamente again.Allow mixture be cooled to room temperature.The refrigerative mixture places ice bath and stirred 1 hour.The filtering separation solid is with the cold solvent lotion of being made up of 67% water and 33% acetone of 25ml.Wash the acetone solvate of dirithromycin standing over night under room temperature under the room temperature with 40ml.

180ml water is added in the wet cake of acetone solvate.With mixture heating up to 70 ℃, stirred 4 hours in 70 ℃ under the inflated with nitrogen.Filtering separation solid immediately is warmed to 70 ℃ water washing with 30ml.Isolating solid spends the night in 40 ℃ of vacuum-dryings.Know through the evaluation of X-ray powder diffraction: this solid is the form ii dirithromycin.

Overall yield: 90.8%

Usefulness: 96.05%

The TRS:3.04%(non-solvative dirithromycin is 4.53%)

Embodiment 10

The separation of form ii dirithromycin

The acetone solvate of 10.0g dirithromycin is stirred in the 100ml water that adds feeding nitrogen down.Make the temperature of reaction mixture rise to 74 ℃, stirred 4 hours down at about 72-75 ℃.With warm mixture vacuum filtration, with 60 ℃ of water washings of about 35ml.Solid spends the night in 50 ℃ of following vacuum-dryings.Identify through X-ray powder diffraction and to know that this solid is the form ii dirithromycin.The ultimate production of reaction is 8.74g(87.4%)

Usefulness: 90.7%

Acetone＜0.03%

Repeat the method for embodiment 8, get following result:

Ultimate production: 8.77g(87.7%)

Usefulness: 93.2%

Acetone＜0.03%

Embodiment 11

The separation of form ii dirithromycin

15g form I dirithromycin is added in the 150ml water.Reaction mixture is heated to 74 ℃, stirred 4 hours down at 74 ℃.The filtering separation solid is with 70 ℃ of washings (40ml * 2).Sample in 25 ℃ of vacuum drying ovens dry 68 hours.Identify through X-ray powder diffraction: product is the form ii dirithromycin.

Productive rate: 97.5g

Usefulness: 96.0%

TRS：3.8%

Embodiment 12

The separation of form ii dirithromycin

5g form I dirithromycin is added in the 25ml ethyl acetate.Solution is heated to 76 ℃, and allowing it seethe with excitement until the reaction mixture volume is about 15ml.Allow reaction mixture be cooled to room temperature, add 20ml water under stirring.The filtering separation solid, washing (25ml * 3), heptane is washed once.Know through the X-ray powder diffraction evaluation: product is the form ii dirithromycin.

Embodiment 13

The separation of form ii dirithromycin

3.01g form I dirithromycin is added in the 15ml ethyl acetate.Reaction mixture is heated to about 76 ℃, and making it keep boiling is about 10ml until the reaction mixture volume.Add the 20ml octane.The filtering separation solid.Sample is dry under room temperature.Know through the X-ray powder diffraction evaluation: product is the form ii dirithromycin.

Overall yield: 95%

Claims

1, the preparation method of form ii dirithromycin, it is included in the solvent that contains 40% to 100% water acetone solvate is made slurries.

2, the preparation method of form ii dirithromycin, it is included in the solvent that contains 40% to 100% water propyl alcohol or 1-butanols solvate is made slurries.

3, the preparation method of form ii dirithromycin, it is included in the solvent that contains 80% to 100% water form I dirithromycin is made slurries, and wherein, solvent temperature is 40 ℃～80 ℃.

4, obtain the method for form ii dirithromycin, it comprises the intermediate product dirithromycin is dissolved in the ethyl acetate, and wherein the temperature of ethyl acetate is a room temperature to 80 ℃.

5, the preparation method of acetone, 1-butanols, 1-propyl alcohol or 2-propyl alcohol solvate, it comprises makes dirithromycin contact with containing the solvent of 0%～80% water with 20% to 100% non-aqueous solvent, and wherein, described non-aqueous solvent is corresponding to the solvate of expectation; Perhaps make the suitable aldehyde and suitably amine reaction that are dissolved in non-aqueous solvent, wherein said non-aqueous solvent is corresponding to the solvate of expectation.